Remote-Control Mechano-Genetics and Epigenetics for Live Cell Manipulation It has been a long held dream for biomedical scientists to dynamically and precisely manipulate molecular activities and cellular functions in distance. Our project aims to bring this dream one step closer to reality, by engineering cellular mechano-sensors to convert the remote ultrasonic signal into intracellular molecular signals, and by engineering genetic transduction modules (GTMs) to relay the molecular signals into dynamically and precisely controlled genetic and epigenetic signals. This remote-controlled mechano- genetics/epigenetics (ReCoM) technology should allow the live cell engineering and manipulation with high spatiotemporal resolution. Our team has ample experience in ultrasound, biosensing, live cell imaging, and molecular and cellular engineering technologies. We have already engineered a prototype ultrasound- activatable cell. Here we propose to systematically develop and optimize the modularized ReCoM technology in three steps: (1) Optimize mechano-sensors that can receive ultrasonic signals via micro-bubbles and convert them into intracellular biochemical signals; (2) Engineer GTMs to relay these specific molecular signals to genetic outputs; (3) Encode the GTMs with locus-specific genetic and epigenetic modulators to allow the remote, dynamic, and precise control of cellular function and fate. This approach should allow the remote-controlled genetic and epigenetic activation in live cells with a high spatiotemporal precision in a non- invasive manner for therapeutic applications. The method should also provide a general approach to dynamically control molecular and cellular functions for biological studies and clinical applications.